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Sulfonamide Compound or Salt Thereof

a technology of sulfonamide and compound, applied in the field of new sulfonamide compound, can solve the problems of poor rnr inhibitory activity, limited effect, and difficult tolerance to hu use, and achieve excellent rnr inhibitory activity and growth inhibitory

Active Publication Date: 2020-12-24
TAIHO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides novel sulfonamide compounds that can inhibit RNR, which is involved in cancer and other diseases. These compounds have excellent RNR-inhibiting activity and can inhibit the growth of cancer cells. As such, they have potential to be developed into anti-tumor agents and therapeutic agents for other diseases where RNR is involved.

Problems solved by technology

Although HU has been used clinically for over 30 years, its RNR inhibitory activity is very weak and its effect is limited (Non-Patent Document 7).
In addition, tolerance to the use of HU is also considered a problem (Non-Patent Document 8).

Method used

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  • Sulfonamide Compound or Salt Thereof
  • Sulfonamide Compound or Salt Thereof
  • Sulfonamide Compound or Salt Thereof

Examples

Experimental program
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Effect test

examples

[0477]The present invention is described below in more detail with examples and test examples, but the present invention is not intended to be limited to these examples.

[0478]Various reagents used in the examples were commercially available products, unless otherwise stated. Biotage Ltd. SNAP-ULTRA (registered trademark) Silica prepacked column was used for a silica gel column chromatography, or Biotage made SNAP KP-C18-HS (registered trademark) Silica prepacked column was used for a reverse phase silica gel column chromatography. HPLC purified by preparative reverse phase column chromatography was performed under the following conditions. Injection volume and gradient was carried out appropriately.

[0479]Column: YMC-Actus Triart C18, 30×50 mm, 5 μm

[0480]UV detection: 254 nm

[0481]Column flow rate: 40 mL / min

[0482]Mobile phase: water / acetonitrile (0.1% formic acid)

[0483]Injection amount: 1.0 mL

[0484]Gradient: water / acetonitrile (10% to 90%)

[0485]AL400 (400 MHz; JEOL (JEOL)) and Mercury...

reference example a1 2

-(1-bromoethyl)-1-fluoro-3,4-dimethylbenzene

[0493]

Step 1

1-(6-fluoro-2,3-dimethylphenyl)ethanol

[0494]After dropping a diethyl ether solution of methylmagnesium bromide (3.0 M, 70 mL) to a THF solution of 6-fluoro-2,3-dimethyl-benzaldehyde (22.0 g) (300 mL) at 0° C., the reaction mixture was stirred at room temperature for 1 hour. Under ice-bath condition, a saturated aqueous ammonium chloride solution (150 mL) was added dropwise, and ethyl acetate (200 mL) was added, and the resultant was separated into different layers. The organic layer was successively washed with HCl (1M, 200 mL), water (200 mL) and saline (200 mL), and then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1-(6-fluoro-2,3 dimethylphenyl)ethanol (23.7 g).

(Step 2)

[0495]Phosphorus tribromide (26.5 mL) was added dropwise at 0° C. to a chloroform solution (120 mL) of 1-(6-fluoro-2,3-dimethylphenyl)ethanol (23.7 g) obtained in the above Step 1, and the reaction solution was stir...

reference examples b2

to B6

[0501]According to the methods of Reference Example B1 Steps 1 and 2 and Reference Example A1 Steps 1 and 2, the following compounds of Reference Examples B2 to B5 were synthesized. Also, according to the methods of Reference Example B1 Step 1, and Reference Example A1 Steps 1 and 2, the compound of Reference Example B6 was synthesized.

TABLE 2Reference ExampleStarting MaterialSynthesized CompoundB2B3B4B5B6

Reference Example C1 7-(1-chloroethyl)-1-methyl-2,3-dihydro-1H-indene

[0502]

[0503]Sodium borohydride (261 mg) was added to a methanol solution (5.0 mL) of 1-(3-methyl-2,3-dihydro-1H-inden-4-yl)ethanone (1.0 g), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was added to water (10 mL) and then extracted twice with ethyl acetate (20 mL). The combined organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (5.0 m...

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Abstract

The present invention provides a novel sulfonamide compound having a ribonucleotide reductase inhibitory activity or a salt thereof, and a pharmaceutical composition containing the same as an active ingredient.A compound represented by Formula (I) [wherein, X1 represents an oxygen atom or the like; X2 represents an oxygen atom; X3 represents —NH—; X4 represents a hydrogen atom or the like; R1 represents —C(R11)(R12)— or the like; R11 and R12 are the same or different and each represents a hydrogen atom or the like; R2 represents an optionally substituted C6-C14 aromatic hydrocarbon group or the like; R3 represents an optionally substituted C6-C14 aromatic hydrocarbon group or the like; R4 represents a hydrogen atom or the like] or a salt thereof.

Description

TECHNICAL FIELD[0001]The present invention relates to a novel sulfonamide compound having a ribonucleotide reductase inhibitory activity or a salt thereof, and a pharmaceutical composition containing the same as an active ingredient.BACKGROUND[0002]Ribonucleotide reductase (hereinafter also referred to as RNR) is composed of a hetero-oligomer of a large subunit M1 and a small subunit M2, and expression of both is required for enzyme activity. RNR recognizes ribonucleoside 5′-diphosphate (hereinafter also referred to as NDP) as a substrate and catalyzes a reduction reaction to 2′-deoxyribonucleoside 5′-diphosphate (hereinafter also referred to as dNDP). Since RNR is a rate-limiting enzyme in the de novo dNTP synthesis pathway, RNR plays an essential role in DNA synthesis and repair (Non-Patent Document 1).[0003]The enzymatic activity of RNR is closely related to cell proliferation, and there is a report that the enzymatic activity is particularly high in cancer (Non-Patent Document 2...

Claims

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Application Information

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IPC IPC(8): C07D271/07C07D413/12A61P35/00C07D417/12C07D491/107C07D413/14
CPCC07D271/07C07D413/12C07D413/14C07D417/12C07D491/107A61P35/00C07D413/06C07D413/10C07D417/06C07D498/04C07D498/08C07D271/113C07D249/10A61K31/4245A61K31/428A61K31/433A61K31/4439A61K31/444A61K31/454A61K31/4709A61K31/4725A61K31/498A61K31/506C07D249/04C07D271/10
Inventor MIYAHARA, SEIJIUENO, HIROYUKIHARA, SHOKIOGINO, YOSHIO
Owner TAIHO PHARMA CO LTD
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